The present invention relates to a new use of a 15-keto-prostaglandin compound as a bile secretion promoter.
Bile is produced by hepatocyte and discharged in the bile duct, and is a colloidal solution containing various and complex ingredients. Producing bile is one of the most important functions in the various liver functions. The bile secreted from the liver is consisting of 97% of water and other ingredients including bile salt, bile pigment, phosphatidylcholine, cholesterol, trace albumins, electrolytes and the like. The main function of the bile is promoting fatty acid digestion and absorption by bile acid. Bile acid has a cholagogic property which induce bile acid-dependent bile secretion. Bile can also be secreted independently of bile acid and said secretion is referred to as bile acid-independent bile secretion. It has been known that reduce of bile secretion which could be caused by blockage of cystic duct, failure of cholecyst constriction, hepatocellular dependent icterus or the like, may cause various failures and diseases such as fatty acid malabsorption.
On the other hand, it has been known that hepatectomy and liver transplantation may cause ischemia-reperfusion cellular injury. Free radical may contribute to etiology of the cellular injury; when free radical is overproduced in the body, it attacks biomolecules and tissues, especially lipids in the biomembrane, to induce cell membrane injury and at the same time it produces lipid peroxide, which causes various failures and diseases in the body. In addition, hepatic failure induced by free radical, which is evoked by ischemia-reperfusion injury, may cause significant reduce of bile secretion. Therefore, to retain liver function, especially bile secreting ability during the liver transplantation process and after implantation of the liver is becoming very important object to be achieved.
Prostaglandins (hereinafter, referred to as PG(s)) are members of class of organic carboxylic acids, which are contained in tissues or organs of human or most other animals, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A): 
On the other hand, some of synthetic analogues of primary PGs have modified skeletons. The primary PGs are classified to PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGls and PGJs according to the structure of the five-membered ring moiety, and further classified into the following three types by the number and position of the unsaturated bond at the carbon chain moiety:
subscript 1: 13,14-unsaturated-15-OH
subscript 2: 5,6- and 13,14-diunsaturated-15-OH
subscript 3: 5,6-, 13,14- and 17,18-triunsaturated-15-OH.
Further, the PGFs are classified, according to the configuration of the hydroxy group at position 9, into a type (the hydroxy group is of a xcex1-configuration) and xcex2 type (the hydroxy group is of a xcex2-configuration).
PGE1, PGE2 and PGE3 are known to have vasodilation, hypotension, gastric secretion decreasing, intestinal tract movement enhancement, uterine contraction, diuretic, bronchodilation and anti ulcer activities. PGF1a, PGF2a and PGF3a have been known to have hypertension, vasoconstriction, intestinal tract movement enhancement, uterine contraction, lutein body atrophy and bronchoconstriction activities.
In addition, some 15-keto prostaglandins (i.e. those having an oxo group at position 15 in place of the hydroxy group) and 13,14-dihydro-15-keto-prostaglandins are known as substances naturally produced by enzymatic actions during in vivo metabolism of primary PGs. 15-keto PGs have been disclosed in the specification of U.S. Pat. Nos. 5,073,569, 5,166,174, 5,221,763, 5,212,324 and 5,739,161. (These cited references are herein incorporated by reference.)
It has been known that a prostaglandin compound having hydroxy group at position 15 has a bile secretion promoting activity. For example, PGE1, PGE2, PGA1, PGF2a, and prostacyclin have been reported to have an cholagogic effect in dogs and cats (J. Physiol. 254, 813-820,1976; J. Surg. Res. 18,391-397,1975; J. Surg. Res. 22,545-553, 1977; Hepatology 2, 275-281, 1986; Hepatology 4, 644-650, 1984; these cited references are herein incorporated by reference.)
In addition, intraportal administration of prostaglandin E1 increased the bile flow in porcine of which liver was replaced by transplantation (Transplantation 64, 205-209, 1997, the cited reference is herein incorporated by reference). Further, in a rat liver transplantation model, addition of TEI-9063, a stabilized PGI2 analogue, to a liver preservation solution improved bile producing activity of the implanted liver (Transplantation 46, 626-628, 1998, The cited reference is herein incorporated by reference.)
The inventor has studied on bioactivities of 15-keto prostaglandin compounds and found that 15-keto-prostaglandin compounds express a significant bile secretion promoting activity, and achieved to the invention. That is, the present invention provides a bile secretion promoting composition comprising a 15-keto-prostaglandin compound as an active ingredient. Said composition can be employed for treatment of liver to be transplanted.
The present invention also provides a method for promoting bile secretion comprising a step of administering an effective amount of a 15-keto prostaglandin compound to a subject having a disease or condition associated with bile secretion deficient.
The present invention also provides a method for treating a liver to be transplanted in a liver transplantation process comprising a step of contacting the liver with a liquid composition comprising a 15-keto-prostaglandin compound.
The present invention further provides use of a 15-keto-prostaglandin compound for producing a pharmaceutical composition for treatment of a subject having a condition or disease associated with bile secretion deficient.
Further more, the present invention provides use of a 15-keto-prostaglandin compound for producing a pharmaceutical composition for treating a liver to be transplanted in a liver transplantation process.
In the present invention, the xe2x80x9c15-keto-prostaglandin compoundsxe2x80x9d (hereinafter, referred to as xe2x80x9c15-keto-PG compoundsxe2x80x9d) may include any of derivatives or analogs (including substituted derivatives) of a compound having an oxo group at 15-position of the prostanoic acid skeleton instead of the hydroxy group, irrespective of the configuration of the five membered ring, the number of double bonds, presence or absence of a substituent, or any other modification in the xcex1 xcfx89 or w chain.
The nomenclature of the 15-keto-PG compounds used herein is based on the numbering system of prostanoic acid skeleton represented in the above formula (A).
The formula (A) shows a basic skeleton of the C-20 carbon atoms, but the 15-keto-PG compounds in the present invention are never limited to those having the same number of carbon atoms. In the formula (A), the numbering of the carbon atoms which constitute the basic skeleton of the PG compounds starts at the carboxylic acid (numbered 1), and carbon atoms in the xcex1-chain are numbered 2 to 7 towards the five-membered ring, those in the ring are 8 to 12, and those in the xcfx89-chain are 13 to 20. When the number of carbon atoms is decreased in the xcex1-chain, the number is deleted in the order starting from position 2; and when the number of carbon atoms is increased in the xcex1-chain, compounds are named as substitution compounds having respective substituents at position 2 in place of the carboxy group (C-1). Similarly, when the number of carbon atoms is decreased in the xcfx89-chain, the number is deleted in the order starting from position 20; and when the number of carbon atoms is increased in the xcfx89-chain, the carbon atoms beyond position 20 are named as substituents. Stereochemistry of the compounds is the same as that of the above formula (A) unless otherwise specified.
In general, each of the terms PGD, PGE and PGF represents a PG compound having hydroxy groups at positions 9 and/or 11, but in the present specification these terms also include those PG related compounds having substituents other than the hydroxy group at positions 9 and/or 11. Such compounds are referred to as 9-dehydroxy-9-substituted-PG compounds or 11-dehydroxy-11-substituted-PG compounds. A PG compound having hydrogen in place of the hydroxy group is simply named as 9- or 11 -dehydroxy compound.
As stated above, the nomenclature of 15-keto-PG compounds is based on the prostanoic acid skeleton. However, in case the compound has a similar partial construction as a prostaglandin, the abbreviation of xe2x80x9cPGxe2x80x9d may be used. Thus, a PG compound of which a chain is extended by two carbon atoms, that is, having 9 carbon atoms in the xcex1 chain is nominated as 2-decarboxy-2-(2-carboxyethyl)-15-keto PG compound. Similarly, a compound having 11 carbon atoms in the xcex1chain is nominated as 2-decarboxy-2-(4-carboxybutyl)-15-keto-PG compound. Further, a 15-keto-PG compound of which xcfx89-chain is extended by two carbon atoms, that is, having 10 carbon atoms in the xcfx89-chain is nominated as 15-keto-20-ethyl-PG compound. These compounds, however, may also be named according to the IUPAC naming system.